Although neuroinflammation is a causative factor in Alzheimer's disease (AD), it is also a consequence of injury in the brain. This results in a continuous feedback loop of inflammation and neuronal/neural cell injury and death that drives neurodegenerative processes. The microglial activation profile over the course of the disease process and how it impacts and/or reflects microglial function is unclear and represents a major gap in our current understanding of the pathogenesis of AD. In this proposal, we will pair histopathological studies on human brain, designed to assess changes in microglial activation at different stages of AD, as well as neuronal ?on? and ?off? signaling, with gene expression analyses of isolated microglial mRNA acquired by laser-capture microdissection (LCM) from the same cases. The findings from these studies will be further analyzed for involvement of key pathways to identify potential causal mechanisms that can be explored in a future RO1 proposal aimed at identifying the mechanism(s) underlying chronic neuroinflammation and functional impairment of microglia in AD, such as major pathways and upstream regulators of microglial inflammatory factors and/or microglia-derived neurotrophic factors that may impact neuronal ?on? and ?off? signaling to microglia that may impair resolution of microglial activation. We anticipate that the findings from this pilot study will significantly challenge the current paradigm of how microglial activation is maintained and its impact on neuronal injury and death in the pathogenesis of AD. This revision application is submitted as a Pilot Project, entitled ?Impaired Microglial Function in Alzheimer's Disease,? to request a supplement to the Center of Biomedical Research Excellence (COBRE) ?Mentoring Research Excellence in Aging and Regenerative Medicine (P20GM103629).?